Exposure to antigen at the neonatal stage supports tolerance of such an antigen during a later encounter. Recently, it has become clear that immunity develops in the newborn but in a form that does not manifest inflammatory reactions, hence, tolerance of the antigen. We now know that the neonatal immune response usually lacks Th1 cells but displays an indubitable bias towards Th2. Most vaccines are not effective in the neonate, possibly, due to poor Th1 immunity. Also, allergies prevail in infants, most likely, due to the Th2 bias of neonatal immunity. Recently, we developed an animal model that overcomes the limitations associated with the neonatal immune system and have begun to investigate the lack of Th1 cells in the newborn. The DO11.10 transgenic mouse, which carry the genes encoding a T cell receptor (TCR) specific for peptide 323-339 of ovalbumin (OVA) and the clonotypic antibody KJ1-26 specific for the TCR-OVA, were used to develop a neonate-to-neonate transfer system suitable for analysis of neonatal immune response ex-vivo. Accordingly, DO11.10 T cells from one-day-old transgenic mice were transferred into one day-old Balb/c mice and a few hours later these hosts were given the antigen. Subsequently, the DO11.10 T cells were traced with KJ1-26 antibody and their responses analyzed. We have evidence that both Th1 and Th2 cells developed upon priming with antigen on the day of birth. Surprisingly, however, when the Balb/c hosts were later challenged with OVA peptide, the Th2 cells responded but the Th1 cells underwent apoptosis. Neutralization of IL-4 of the Th2 mates prevented death of the Th1 cells and restored their recall responses. Moreover, we have separated primary Th1 and Th2 cells on the basis of cytokine secretion and found that the primary neonatal Th1 specifically up-regulated IL-13 receptor (IL-13R) alpha 1 chain. More important, when IL-4 was neutralized the up-regulation of IL-13R alpha 1 was inhibited, the cells remained alive and developed Th1 type responses. We propose to knockout IL-13R alpha 1 gene and utilize the resulting IL-13R-deficient mouse to address the postulate that IL-4 utilizes a developmentally expressed nonconventional receptor (incorporating IL-13R alpha 1 chain) to control neonatal tolerance. Also, we propose to generate IL-13R neutralizing monoclonal antibodies to perform blockade experiments and evaluate the contribution of IL-13R to tolerance at the developmental level.